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Antimalarial activities of new pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives.

ABSTRACT: WR227825 is an antimalarial pyrroloquinazolinediamine derivative with a high potency but a low therapeutic index. A series of carbamate, carboxamide, succinimide, and alkylamine derivatives of WR227825 were prepared to search for compounds with an improved therapeutic index. The new acetamides and imide showed potent cell growth inhibition against four clones of Plasmodium falciparum (D-6, RCS, W-2, and TM91C235), with a 50% inhibitory concentration of approximately 0.01 ng/ml, and were highly active against Plasmodium berghei, with 100% cure at doses from <0.1 mg/kg of body weight to 220 mg/kg. The carbamates and alkyl derivatives, however, showed weak activity against Plasmodium falciparum cell growth but were highly efficacious in tests against P. berghei by the Thompson test. The best compounds, bis-ethylcarbamate (compound 2a) and tetra-acetamide (3a) derivatives, further demonstrated high potency against the sporozoite Plasmodium yoelii in mice and P. falciparum and Plasmodium vivax in aotus monkeys. Against the AMRU-1 strain of P. vivax, which has four dihydrofolate reductase mutations and is highly resistant to antifolates, tetra-acetamide 3a cured the monkeys at doses of 1 and 3 mg/kg. Compound 2a cured only one out of two monkeys at 3 mg/kg. The results indicated that the new derivatives 2a and 3a not only have retained/improved the antimalarial efficacy of the parent compound WR227825 but also were less toxic to the animals used in the tests.

SUBMITTER: Guan J

PROVIDER: S-EPMC1315943 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThere are only limited publications devoted to the synthesis of especially thiazolo[3,2-a]quinazoline which involved reaction of 2-mercaptopropargyl quinazolin-4-one with various aryl iodides catalyzed by Pd-Cu or by condensation of 2-mercapto-4-oxoquinazoline with chloroacetic acid, inspite of this procedure was also reported in the literature to afford the thiazolo [2,3-b] quinazoline. So the multistep synthesis of the thiazolo[3,2-a]- quinazoline suffered from some flaws and in this study we have synthesized a novel class of thiazoloquinazolines by a simple and convenient method involving catalysis by 1,4-diazabicyclo[2.2.2]octane (DABCO).ResultsA new and convenient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5-diones 9a-i was established through the reaction between methyl-2-(2-thio-cyanatoacetamido)benzoate (4) and a variety of arylidene malononitriles 8a-i in the presence of DABCO as a mild and efficient catalytic system via a Michael type addition reaction and a mechanism for formation of the products observed is proposed. Moreover 4 was converted to ethyl-2-[(4-oxo-3,4-dihydroquinazolin-2-yl)thio]acetate (10) upon reflux in ethanol containing DABCO as catalyst. The latter was reacted with aromatic aldehydes and dimethylformamide dimethylacetal (DMF-DMA) to afford a mixture of two regioselectively products with identical percentage yield, these two products were identified as thiazolo[3,2-a]quinazoline 9,13 and thiazolo[2,3-b]quinazoline 11,12 derivatives respectively. The structure of the compounds prepared in this study was elucidated by different spectroscopic tools of analyses also the X-ray single crystal technique was employed in this study for structure elucidation, Z/E potential isomerism configuration determination and to determine the regioselectivity of the reactions.ConclusionA simple and efficient one-pot synthesis of a novel class of 2-arylidene-2H-thiazolo[3,2-a]quinazoline-1,5-diones 9a-i was established through DABCO catalyzed Michael type addition reaction. In addition many fused quinazoline and quinazoline derivatives were synthesized which appeared as valuable precursors in synthetic and medicinal chemistry.

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Antimalarial activities of new pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives.

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